1. Field of the Invention
The present invention relates to a drug delivery system, especially to a drug delivery system targeting estrogen receptor over-expressed cells.
2. Description of Related Art
Estrogen receptors (ER, herein after) are mainly expressed in ovarian, uterus and liver cells, and are found over-expressed in certain tumor cells, such as breast cancer, ovarian cancer, uterus cancer and prostate cancer. More and more studies since 1981 have revealed that the expression of ERs are high not only in nuclei but also on cell membranes for signal transduction.
Tamoxifen (Tam, herein after), an antiestrogen known to have high affinity for ERs, is a frequently used drug for treating and preventing breast cancer in clinical trials. Some researchers have synthesized a variety of Tam derivatives for imaging abnormal tissues with high ERs expression, such as breast cancer. However, except as a chemical therapeutic agent and imaging agent, there is no such application for Tam and its derivatives to serve as a ligand in drug delivery systems.
The conventional drugs, such as small molecule drugs, protein drugs, peptide drugs and nucleotides, or nanoparticle drug delivery systems, such as liposomes, polymers and emulsions, cannot specifically target to target-cells. Therefore, a specific ligand is needed for delivering the drugs or nanoparticle drug delivery systems to target cells with specific receptors, so as to increase the efficiency of the drugs and lower the side effects. Today, no targeted drugs are found on the market. Theoretically, it is possible to practice targeted delivery of drugs by employment of antigen/antibody conjugation, but the antigen/antibody may induce the immunogeneicity in the host, which may subsequently results in unpredictable consequences.
The term “targeted delivery system” is used to describe the system utilizing ligands that bind to the specific target receptors on target cells so as to guide the drugs or nanoparticles into the target cells. The examples of ligands include antibodies, antibody fragments, peptides or small molecule compounds that can be conjugated with drugs or attached to the surface of the nanoparticles. The receptors should be located on the surface of the target cells, and can trigger endocytosis after binding with the ligands. There are about 15 papers since 1981 to 2002 proving that ERs exist not only in the nuclei but also on the plasma membrane. V. D. Ramirez further proved that the binding of Tam with estrogen receptors could trigger endocytosis in HepG2 cells. This evidence implied the possibility of applying Tam as a targeted ligand for targeted delivery of drugs.
On the other hand, Tam is a frequently used drug for breast cancer treatment. However, there is no known application of Tam as a targeted ligand other than as a cancer-imaging agent.
To summarize, we hypothesize that Tam may be applicable as a targeted ligand, which can guide drugs or nanoparticle drug delivery systems to the surface of target cells and capable of inducing endocytosis so as to deliver certain specific matters into target cells.